This project investigates how animals detect and respond to changes in O2 availability, focusing on acute hyperoxia sensing (IL-17 signaling), acute hypoxia sensing, and anoxia tolerance. Using C. elegans as a model system, we identified genetic and molecular mechanisms that regulate O2 adaptation, revealing previously uncharacterized pathways that integrate transcriptional regulation, metabolism, and mitochondrial and lysosomal signaling.
IL-17 signaling is best known for its role in immune responses. Our work demonstrates that it is involved in a variety of cellular processes such as acute hyperoxia (~21%) responses, stress adaptation and cellular homeostasis in C. elegans. We mapped the transcriptional network downstream of IL-17 signaling, identifying key transcription factors and co-regulators that control gene expression in response to IL-17 pathway activation. By combining genetic analysis with transcriptomic profiling, we uncovered a set of IL-17 signaling regulators, including nuclear hormone receptors, transcriptional coactivators, and chromatin modifiers. These factors act together to modulate lipid metabolism, lysosomal activity, and cellular stress responses. Notably, the nuclear hormone receptor plays a central role in coordinating gene expression changes downstream of IL-17. These findings suggest that IL-17 signaling fine-tunes metabolic and stress-response pathways, providing a link between immune-like signaling and cellular adaptation processes.
In addition to our interest in hyperoxia responses, our research focuses on identifying the molecular and neural mechanisms underlying acute detection of low O2 in C. elegans. We found that exposure to hypoxia (~1%) triggers a rapid behavioral response, which is regulated by a network of sensory neurons, neuropeptides, and intracellular signaling pathways. Through genetic screening, we identified several key regulators of acute hypoxia responses, including G-protein-coupled receptors (GPCRs), cyclic nucleotide signaling molecules, and mitochondrial components. A major discovery was that cGMP signaling interacts with mitochondrial ROS to modulate O2 sensing, highlighting a pivotal role of metabolic signals in hypoxia detection. Further investigations revealed several additional key molecules, including K+ channels and H2S synthesizing enzymes, involved in acute hypoxia sensing. The identification of these molecules allows us to map the signal transduction from mitochondrial ROS to the membrane K+ channels upon acute drop of O2, addressing a long-standing puzzle in acute sensation of hypoxia.
Unlike hypoxia sensing, which requires rapid behavioral adaptations, surviving anoxia (complete oxygen deprivation) depends on long-term metabolic and physiological adjustments. Our research identified key transcription factors and metabolic regulators that contribute to anoxia resistance. These transcription factors control gene expression that are critical for animals to survive under extremely low O2 conditions, while a conserved potassium channel protects against anoxia-induced damage by maintaining cellular ion homeostasis and sustaining glycogen storage.
Our research on O2 sensing and anoxia tolerance in C. elegans sheds light on the fundamental mechanisms governing cellular responses to low O2. These findings contribute to a broader understanding of hypoxia adaptation, metabolic regulation, and stress responses across biological systems.
